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Nucleic Acids Research, 1982, Vol. 10, No. 4 1379-1387
© 1982


MOLECULAR BIOLOGY

Comparative effects of the 5'-triphosphates of 9-ß-(2'azido-2'-deoxy-D-arabinofuranosyl)adenine and 9-ß-D-arabinofuranosyladenine on DNA polymerases from L1210 leukemia cells

H.S. Allaudeen, J.W. Kozarich and A.C. Sartorelli

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine New Haven, CT 06510, USA

Received December 22, 1981. Accepted January 28, 1982.

9-ß(2'-Axido-2'-deoxy-D-arabinofuranosyl)adenine (arazide) causes greater and significantly more persistent inhibition of [3H]-thymidine incorporation into the DNA of neoplastic cells than the related agent 9-ß-D-arabinofuranosyladenine (araA). To elucidate the mechanism(s) responsible, we compared the effects of arazide and araA 5'-triphosphates on DNA polymerases {alpha} and ß of L1210 leukemia cells. Both nucleoside triphosphate analogs inhibited DNA polymerase {alpha} activity by competing with dATP; only araATP was inhibitory to DNA polymerase ß. Arazide triphosphate was at least four times more active than araATP as an inhibitor of DNA polymerase {alpha}. Preincubation of DNA polymerase {alpha} with either agent did not result in enzyme inactivation. The results suggest that interference with DNA polymerase {alpha} activity by arazide triphosphate may be in part responsible for the inhibition of DNA synthesis produced by arazide in neoplastic cells.


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